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BC Chemists Speed Up Activity of Valued Catalyst

lewis bases work in concert to produce prized chiral molecules

CHESTNUT HILL, Mass. (July 2013) – A new, computationally-inspired approach has led a team of Boston College chemists to re-conceptualize a highly valued catalytic process, dramatically increasing the efficiency of a chemical transformation that selectively produces chiral, or handed, molecules prized for medical and life sciences research, the team reports in the current online edition of the journal Nature Chemistry.

The new approach allows for reducing the reaction time to less than an hour, down from a period of two to five days, the team reports. That gain was accompanied by a similarly dramatic reduction in catalyst loading, producing a cleaner and more efficient reaction via a procedure known as enantioselective alcohol silylation.

Amir Hoveyda

Based on a computational projection, the team employed the high-risk approach of using co-catalysts to achieve marked gains in the reaction. Co-catalysts conflict because of their overlapping properties and functions, making it difficult to control the intended reaction. In this case, the seemingly competitive co-catalysts work in concert.

“The use of co-catalysts can be tricky, especially in procedures intended to deliver handedness in the molecules you want your reaction to produce,” said one of the lead authors, Amir Hoveyda, the Joseph T. and Patricia Vanderslice Millennium Professor of Chemistry at Boston College. “What we’ve shown is that in this procedure you can take two co-catalysts, which on the surface are competing with one another, and effectively keep them from interfering with one another.”

Hoveyda and Professor of Chemistry Marc Snapper, the other lead author, have worked since 2006 on this method of catalysis. These catalysts, originally developed in their laboratories seven years ago, are valued for producing reactions that offer a high level of enantioselective purity – the synthesis of mirror-image, or handed isomers – which are crucial building blocks for biological and medical research.

But a relatively slow reaction time of two to five days had stymied the scientists since reporting an earlier breakthrough in 2006, the latest advance in a research partnership that extends nearly two decades. But the addition of computational chemist Fredrik Haeffner to the team two years ago led to new models and insights into how to further refine the procedure, Hoveyda said.

“We could never have done this without the power of computational chemistry that Fredrik brings to the team,” said Hoveyda. Haeffner is a senior research associate in the Hoveyda group in the Chemistry Department at Boston College and a former scientist at the National Institutes of Standards and Technology.

Marc Snapper

Based on Haeffner’s calculations, the research team, which included BC graduate students Nathan Manville and Hekla Alite, employed the co-catalyst model involving two Lewis base molecules – adding an achiral molecule to an already present chiral molecule. These Lewis bases, discovered nearly 100 years ago, are seemingly competitive as they both seek to shed a pair of electrons to a receptive Lewis acid. Remarkably, however, rather than compete, these co-catalysts operate in concert, with the chiral molecule activating alcohol and the additional achiral molecule – from commercially available 5-ethylthiotetrazole – activating silicon.

Identification of the positive influence of ethylthiotetrazole proved to be the key component of the discovery, giving the team the ability to fine-tune the reaction and effectively control the interplay between the co-catalysts. Together, the Lewis bases served as a closely related Bronsted base – an entity that absorbs a proton – to allow the catalyst to work faster yet retain high enantioselectivity.

“The bottom line is the reaction goes a lot faster,” said Snapper. “The practical advance is adding the tetrazole, which greatly accelerated the pace of the reaction by doing a much better job activating the silicon reaction partner.”

The authors suggest that the new conceptualization of the catalyst could lead to the development of new processes that require separate and independently operational Lewis basic co-catalysts. The findings indicate the new strategy can overcome the overlapping functions of the co-catalysts and eliminate detrimental effects on the production of new molecules with high enantioselectivity.

The full report, “Enantioselective silyl protection of alcohols promoted by a combination of chiral and achiral Lewis basic catalysts,” can be found at: